FMS is the receptor for macrophage colony stimulating factor (M-CSF or CSF-1) and is
essential for the differentiation and survival of most macrophages, microglia and
osteoclasts Infiltration of macrophages and high levels of M-CSF in serum are
associated with poor prognosis in human breast, ovarian and endometrial cancers.
Consequently, inhibitors of FMS have considerable therapeutic potential for the treatment
of cancer, as well as macrophage-mediated inflammatory disease and bone disorders
caused by excessive osteoclastogenesis .
Here I report the identification of four clinically advanced small molecule kinase
inhibitors which can also target FMS, as shown by various biochemical and cell-based
assays. The inhibitors I identified are imatinib, nilotinib, tandutinib and dasatinib
(IC50s = 600, 250, 400 and 0.5 nM, respectively), where the IC50 values refer to
inhibition of FMS-dependent cell growth.
All of these inhibitors effectively inhibited osteoclastogenesis at concentrations
expected to be achieved in patients and nilotinib was a particularly potent inhibitor
(IC50 = 50 nM) indicating that nilotinib is a strong candidate for treatment of diseases
where osteoclasts are over activated such as osteoporosis and osteolytic bone disease.
Dasatinib was found to be a potent inhibitor of tumour associated macrophages
derived from ovarian tumour ascites (IC50 = 0.5 nM) which is similar to the
concentration required to inhibit FMS and within concentrations considered to be
achieved in vivo.

Using these FMS inhibitors I have also confirmed that the downregulation of the FMS
receptor in response to ligand binding is independent of kinase activity and instead
requires a structural change in the receptor. Intriguingly, at least two tyrosine
autophosphorylation sites of FMS are still phosphorylated in the presence of some of
these inhibitors and therefore in the absence of FMS kinase activity. This implies that
other kinases may be involved in FMS activation.